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3 Tools for Assessing Spinal Cord Injury and Repair
Pages 64-94

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From page 64...
... They also provide researchers with the tools that they need to examine changes in the spinal cord at the molecular and structural levels, for example, improving knowledge of the inhibitory conditions that serve as barriers to neuronal regeneration. This chapter describes the important genetic and in vitro tools that have been developed to advance spinal cord injury research; the key animal models that are used to mimic human spinal cord injuries and the major limitations of the existing animal models; and the outcome measures that have been developed to assess spinal cord injuries and the effectiveness of experimental therapies, including the development of imaging technologies.
From page 65...
... . Animal Models for Molecular and Genetic Studies Models consisting of multiple-transgenic animals have been developed to investigate molecular mechanisms and to identify the molecules critical for specific processes (Table 3-1)
From page 66...
... ANIMAL MODELS OF SPINAL CORD INJURY Animal models allow in-depth investigation of the anatomical and molecular changes that occur in response to a spinal cord injury at a level of detail that would not be possible or ethical in studies with humans. These insights are critical for the design and interpretation of the results of studies with humans.
From page 67...
... . Further TABLE 3-2 Value of Animal Models for Spinal Cord Injury Research · Allows in-depth investigation of the anatomical changes that occur in response to an injury · Regeneration of axonal tracts between the brain and the spinal cord can be studied in detail · Individual components of the complex neural circuitry required for sensory perception and motor control can be examined · Factors that influence DNA and proteins can be characterized · Provides a means to examine the effects of specific genes · Provides a tool to identify and test the efficacies of potential therapeutic agents and targets · Identifies clinical end points that can be used to assess the efficacies of therapeutic agents
From page 68...
... is different and presents its own set of challenges; therefore, each requires its own standard animal model that reliably mimics the complications experienced by individuals with that type of spinal cord injury. A number of animal models have been developed, including models that mimic compression, contusion, and transection (Table 3-4)
From page 69...
... TOOLS FOR ASSESSING SPINAL CORD INJURY AND REPAIR 69 TABLE 3-4 Commonly Used Animal Models of Spinal Cord Injury Animal and Injury Modeled Primary Utility and Potential Issues Primate · Test the safety and efficacies of therapies transection · Determine the role of the central pattern generator in bipedal animals · Ethical complications with the use of primates · High cost of animal maintenance · Limited number of animals that can be prepared for experimentation · Spatial arrangement of the tracts differs from that in humans Cat · Examine and define spinal cord circuitry and contusion, the central pattern generator transection · Central pattern generator may have different amounts of brain regulation compared with that in humans · Spatial arrangement of the tracts differs from that in humans · Chromosomes and genes are organized differently from those in humans Mouse · Investigate molecular and anatomical changes contusion, that occur in response to injury; however, compression, mice respond differently than humans to transection, spinal cord injury transgenic, · Examine specific molecular targets for microlesion potential therapeutic targets formation · Modify genes to test the effect on restoration or loss of function · Difficult to assess upper extremity function · Genetic variability in injury response, including scar formation · Differences in scale size of spinal cord between mice and humans · Spatial arrangement of the tracts differs between mice and humans · Chromosomes and genes are organized differently from those in humans Rat · Investigate molecular and anatomical changes contusion, that occur in response to injury compression, · Difficult to assess upper extremity function transection, · Differences in scale size of spinal cord in rats microlesion versus humans formation · Chromosomes and genes are organized differently from those in humans NOTE: Contusion refers to a bruising of the spinal cord. Transection models are used to simulate lacerations to the spinal cord.
From page 70...
... Three impactors are widely accepted as standard methods for the delivery of contusion injuries to rodents: the Ohio State University (OSU) impactor, the Infinite Horizons device, and the Multicenter Animal Spinal Cord Injury Study (MASCIS)
From page 71...
... Each group removed a spe cific part of a mouse's chromosome that is responsible for Nogo, with the hypoth esis that if Nogo is responsible for inhibiting neurons from growing, then its removal would facilitate regeneration after a spinal cord injury. However, the experiments found contradictory results.
From page 72...
... (B) The diameter of the human spinal cord is also much larger than that of the rat spinal cord.
From page 73...
... Furthermore, there is no standard laboratory animal model that spinal cord injury researchers can use to examine fine motor control of the upper extremities or the loss of the sensory modality proprioception, which is responsible for limb position and immediately varying the degree of muscle contraction in response to external stimuli. When individuals with spinal cord injuries lose their proprioception, they are unable to move freely and interact comfort
From page 74...
... Similarly, it is difficult for preclinical researchers to consistently assess progress in laboratory animal experiments and to determine the amount of progress, if any, that results from natural recovery, drug therapy, surgical intervention, or rehabilitation. Outcome Measures Used to Assess Spinal Cord Injury in Animal Models Tests developed to examine the recovery of function in laboratory animals have been designed primarily to examine motor function (Table 3-5; Appendix D)
From page 75...
... , an open-field locomotor test for mice · Is an adaptation of rat BBB scale to examine the recovery of hind-limb locomotor function · Assesses walking, not other movements requiring coordinated spinal cord activity · Does not assess pain, bowel, bladder, or sexual function Neuronal activity assessment by electrophysiology · Assesses MEPs or SSEP · Stimulates corresponding cortical areas of the brain and records response in target nerves to see if connections are still functional · Correlates to impairment of locomotor activity · Is noninvasive · Neuronal activity may not correlate with functional changes · Hard to assess subtle but critical improvements to circuitry · Does not directly assess pain, bowel, bladder, or sexual function Forepaw withdrawal · Investigates recovery of heat perception · The forepaw is placed on a heat block and the time that it takes for the animal to withdraw it is measured · Forepaw withdrawal requires motor function · Does not assess pain, bowel, bladder, or sexual function Directed forepaw reaching · Looks at coordinated limb and muscle movement · Requires rats to reach under a barrier and pick up food with forepaws · Limited scale for assessment · Does not assess pain, bowel, bladder, or sexual function Morphological assessment of recovery Histology · Is used to look at the morphology of axons and assess the degree of tissue sparing, injury, and recovery Continued
From page 76...
... However, the scale has several limitations as it assesses only the functional recovery of the hind limbs and not other elements of fine motor control that are required for coordinated activity regulated by the spinal cord; does not examine the recovery of sensory modalities, including pain and temperature sensations; does not assess other complications that arise as a result of spinal cord injuries, including bowel and bladder function, pain, or sexual capacity; and is not linear. Outcome Measures Used to Assess Spinal Cord Injury in Humans Clinicians have available more than 30 assessment tests and surveys that they can use to examine individuals with spinal cord injuries (see Appendix D)
From page 77...
... The full potential uses of biomarkers for spinal cord injury research include the following: · Diagnosis and prognosis. The expression profile of a biomarker, especially proteins, could provide clinicians with information that aids in establishment of a diagnosis and a prognosis of a patient's injury.
From page 78...
... · Specific to changes in progression indicator; otherwise, the effects of other changes in the biomarker (e.g., compensatory changes related to drugs used to treat the injury or to agent under study in a clinical trial) should be known so that suitable adjustments in the analysis of clinical trial data can be made · Low signal-to-noise ratio for the biomarker measure · Safe and tolerable and should not require maneuvers that could unblind the study Other desirable properties of · Relatively inexpensive and easy to use a biomarker measure used as · Capable of being used in repeated studies with a a progression indicator particular individual with a spinal cord injury Data needed to support the use · Data from longitudinal studies should be of progression indicator or available for a sufficient number of individuals biomarker measurement for with spinal cord injuries to allow an informative application to a clinical trial assessment of the distributional properties (e.g., for study of spinal cord injury mean and variance)
From page 79...
... The analysis of changes in specific gene products that are up- and down-regulated in response to a spinal cord injury could also provide researchers with a tool to identify specific targets that could be used for future drug development. Understanding of the molecular and cellular mechanisms involved in spinal cord injuries may permit identification of specific targets for therapeutic benefit.
From page 80...
... , glutamate receptors, GABA receptors (­) , glutamate transporter lyze changes to individual or multiple proteins have the potential to provide investigators with information about cellular responses to spinal cord injuries.
From page 81...
... Regulation of Fra-1, NGFI-A Fra-1, NGFI-A None DNA synthesis NOTE: Analysis of proteomic and DNA gene array studies identified significant changes in gene expression in response to a spinal cord injury. Classification of these genes into specific functions provides further insight into the processes that are changing.
From page 82...
... EDRN also helped to establish standards for the development and evaluation of biomarkers and guide the process of biomarker discovery related to cancer biology. Using EDRN as a model, the spinal cord injury community can transfer many of the recommendations and strategies developed to facilitate progress on cancer research for spinal cord injury research.
From page 83...
... for studies designed to define gene expression profiles following traumatic spinal cord injuries. Because the technologies used to identify biological markers can detect small but significant changes in gene expression, they are sensitive to slight variations in protocol.
From page 84...
... . The National Institutes of Health has recommended that fMRI techniques be developed to assess the degree of loss and recovery of sensation in rodents with contusion injuries to their spinal cords (Hofstetter et al., 2003; NINDS, 2004)
From page 85...
... Magnetic resonance technology can be adapted to provide more than diagnostic information about the structural changes occurring in response to a spinal cord injury. In 2001, Bulte and colleagues used magnetic resonance to track oligodendrocyte stem cells that were prelabeled with super paramagnetic iron oxide nanocomposites, which are small beads invisible to the naked eye that can be detected by MR technology (Bulte et al., 1999, 2001)
From page 86...
... . However, refinements to PET scans could provide important information about the cellular states of the injury, such as gene activation or suppression in response to the injury; this would provide physicians with the ability to quantify responses to different spinal cord injury treatments (Brooks et al., 2003)
From page 87...
... With improvements in the current technology, the use and improvement of near-infrared markers might also provide researchers with a means to monitor the progression of a spinal cord injury and recovery in laboratory animals. Multidisciplinary Research and Bringing Molecular Imaging to the Clinic The promise of molecular imaging technologies can be realized only if the technologies can be successfully transferred to the clinical setting.
From page 88...
... These programs, along with support mechanisms sponsored by the National Institute of Biomedical Imaging and Engineering, provide mechanisms and model systems that can be used to promote the cooperative development of new imaging systems for spinal cord injury research and treatment. RECOMMENDATIONS Recommendation 3.1: Increase Training Efforts on Standardized Re search Tools and Techniques Spinal cord injury researchers should receive training in the use of standardized animal models and evaluation techniques.
From page 89...
... Particular emphasis should be placed on: · improving imaging technologies to allow real-time assessment of the current state and progression of the injury; · identifying biomarkers that can be used to monitor the progres sion of the injury and recovery; · developing additional animal models to explore the progression of spinal cord injury and repair; · establishing standardized sets of functional outcome measures for the evaluation of experimental therapies for each type and each stage of spinal cord injury in animal models; and · enhancing functional assessment techniques to examine motor function as well as secondary complications, including pain and depres sion of the immune system. REFERENCES AANS (American Association of Neurological Surgeons)
From page 90...
... 2001. Gene expression profiling of acute spinal cord injury reveals spreading inflammatory signals and neuron loss.
From page 91...
... 2002. Genetic influences on secondary degeneration and wound healing following spinal cord injury in various strains of mice.
From page 92...
... 2000. Validation of the weight-drop contusion model in rats: A comparative study of human spinal cord injury.
From page 93...
... 2002. Embryonic interme diate filament, nestin, expression following traumatic spinal cord injury in adult rats.
From page 94...
... 1996. Genetic influences on cellular reactions to spinal cord injury: A wound-healing response present in normal mice is impaired in mice carrying a mutation (Wld(s)


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